Abstract Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. ...However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.
Introduction: Propofol infusion syndrome (PRIS) is rare but a potentially lethal adverse event. The pathophysiologic mechanism is still unknown.
Patient concerns: A 22-year-old man was admitted for ...the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings, acute kidney injury, hyperkalemia and severe rhabdomyolysis.
Diagnosis and interventions: The patient was transferred to our intensive care unit (ICU) on suspicion of PRIS. Administration of noradrenaline and renal replacement therapy and fasciotomy for compartment syndrome of lower legs due to PRIS-rhabdomyolysis were performed.
Outcomes: The patient gradually recovered and was discharged from the ICU on day 30. On day 37, he had repeated sinus bradycardia with pericardial effusion in echocardiography. Cardiac
18F-FDG PET on day 67 demonstrated heterogeneous
18F-FDG uptake in the left ventricle. Electron microscopic investigation of endomyocardial biopsy on day 75 revealed mitochondrial myelinization of the cristae, which indicated mitochondrial damage of cardiomyocytes. He was discharged without cardiac abnormality on day 192.
Conclusions: Mitochondrial damage in both morphological and functional aspects was observed in the present case. Sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.
The number of patients with chronic heart failure (CHF) is increasing in Japan. Because there is a shortage of medical professionals to address the demands of an aging society, it is important for ...CHF patients to receive appropriate treatment from medical professionals in their own neighborhoods. Multidisciplinary care, involving physicians, nurses, pharmacists, care managers, et al., is indispensable for providing safe, appropriate home medical care for CHF patients. In multidisciplinary care, pharmacists play an important role, especially in improving patient adherence to CHF treatment regimens. Pharmacists are also expected to participate actively in the improvement of patients' quality of life and the avoidance of hospital readmission. However, team medicine for CHF treatment is in its nascent stage, and the system for providing multidisciplinary care is still under development. It is important to discuss the present situation and the issues facing multidisciplinary care for CHF treatment. In particular, we need to enhance the significance and role of pharmacists in providing successful multidisciplinary care. In this symposium, I highlight the new role of pharmacists in home medical care for CHF treatment and introduce the pharmaceutical education program of Chiba University.
Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal–regulated ...kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH2-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch–induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
To determine optimum periods for 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) examination in subjects with suspected acute myocarditis, we compared 18F-FDG PET with endomyocardial ...biopsy (EMB) using the latest definition of 18F-FDG PET for inflammatory left ventricular (LV) myocardium.
Retrospective analysis of 29 subjects (18 male, 48±18years) who have symptoms or LV dysfunction underwent both 18F-FDG PET (Advance NXi, GE-Healthcare) under fasting conditions and EMB from LV posterior wall within 3months.
When we defined 18F-FDG PET positive inflammatory LV posterior wall as ‘focal on diffuse’ pattern, sensitivity, specificity, and positive predictive values (PPV), and negative predictive values (NPV) of 18F-FDG PET for detecting active inflammatory LV posterior wall compared with EMB were 46.2, 81.3, 66.7, and 65.0%, respectively. Receiver operating characteristic curve of periods (days) between onset of clinically suspected acute myocarditis and performance of 18F-FDG PET for detecting inflammatory LV posterior wall demonstrated 17days as a best cut off values with area under the curve (0.497, P=0.982) with sensitivity=21.1% and specificity=100%. Sensitivity, specificity, PPV and NPV of 18F-FDG PET for detecting inflammatory LV posterior wall on EMB were all 100% when 18F-FDG PET was performed at 1–14days after onset of suspected acute myocarditis.
In our definition, 18F-FDG PET showed excellent agreement with EMB for detecting active inflammatory LV posterior wall in subjects with clinically suspected active acute myocarditis. If possible, 18F-FDG PET should be performed within 14days after the onset to maintain high diagnostic accuracy compared with EMB.
The Telmisartan and Losartan Cardiac Evaluation Trial, a multicenter, prospective, randomized, open-labeled, blinded-endpoint trial, was designed to compare the effects of two angiotensin II receptor ...blockers (ARBs), telmisartan and losartan, on cardiovascular protection in Japanese patients with mild to moderate essential hypertension. We compared the effects of telmisartan and losartan on left ventricular (LV) hypertrophy, cardiac function, atherosclerosis of carotid arteries and surrogate markers related to the actions of peroxisome proliferator-activated receptor-γ. A total of 58 patients were enrolled in the present trial and the follow-up period was 1 year. There were no significant differences in blood pressure (BP) levels between the telmisartan group and the losartan group throughout the trial. The percentage of the patients treated with ARB monotherapy was significantly higher in the telmisartan group compared with the losartan group. In addition, the progression of intima-media thickness of common carotid artery was significantly inhibited in the telmisartan group compared with the losartan group. Neither group experienced significant changes in cardiac function and LV mass index. There were no differences between the groups with respect to changes in surrogate markers such as serum adiponectin, creatinine, homeostasis model assessment index, plasminogen activator inhibitor-1 and high sensitivity C-reactive protein. Although BP levels were equal and well controlled in both groups, telmisartan showed more protective vascular effects than losartan.
It is still not clear whether loss of cardiomyocytes through programmed cell death causes heart failure. To clarify the role of cell death in heart failure, we generated transgenic mice (TG) that ...express human diphtheria toxin receptor in the hearts. A mosaic expression pattern of the transgene was observed, and the transgene-expressing cardiomyocytes (17.3% of the total cardiomyocytes) were diffusely scattered throughout the ventricles. Intramuscular injection of diphtheria toxin induced complete elimination of the transgene-expressing cardiomyocytes within 7 days, and ∼80% of TG showed pathophysiological features characteristic of heart failure and were dead within 14 days. Degenerated cardiomyocytes of the TG heart showed characteristic features indicative of autophagic cell death such as up-regulated lysosomal markers and abundant autophagosomes containing cytosolic organelles like cardiomyocytes of human dilated cardiomyopathy. The heart failure-inducible TG are a useful model for dilated cardiomyopathy, and provided evidence indicating that myocardial cell loss through autophagic cell death plays of a causal role in the pathogenesis heart failure.
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•This paper develops a solver based on the open source toolbox OpenFOAM.•The coupled heat transfer between gas, catalyst, reactor, and coolant is solved.•Two-temperature model ...calculates the temperature of gas and catalyst is adopted.•The solver coupled with a reaction model reproduces observed temperature profile.
Methanation is one of the promising candidates in developing CO2 utilization technology. Because of its exothermic behavior, the methanation reactor must be carefully designed to avoid the hotspots formation and the deterioration of catalysts. This study presents a numerical study simulates heat transfer between the reacting gas in a porous catalyst layer, reactor tube, and coolant in a shell-and-tube reactor. The aim is to develop a tool can predict the hotspots appearing in the reactor used in CO2 methanation. The open-source toolbox OpenFOAM is adopted and modified. The catalyst bed is assumed to be a continuous porous medium. The results revealed that the solver captures the trends of temperature profiles along both axial and radial directions. The maximum catalyst temperature predicted by this solver is in good agreement with the experimental result, indicating that the solver is a promising tool for future applications in reactor optimization and heat management.
The homeobox transcription factor CSX/NKX2.5, which is a vertebrate homologue of the Drosophila gene tinman, is essential for cardiac development. It is expressed in the early cardiac mesoderm and in ...heart muscle lineage throughout life. Homozygous deletion of CSX/NKX2.5 causes early embryonic lethality in mice because cardiac development is arrested at the linear heart tube stage. Heterozygous mutation of human CSX/NKX2.5 has been associated with various congenital heart diseases such as atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, and tricuspid valve abnormalities, including Ebstein's anomaly. Additionally, CSX/NKX2.5 mutation causes atrioventricular (AV) conduction block with or without associated congenital heart diseases. Ten different heterozygous mutations have been already reported and a new point mutation, which is a C-to-A transition (Cys264ter) at nucleotide 901 of CSX/NKX2.5, results in the production of a truncated protein occurring COOH-terminal to the homeodomain of CSX/NKX2.5. The mutation was found in a patient with familial ASD and first-degree AV block; 4 members from 3 generations had secundum-type ASD and first-degree AV block. (Circ J 2002; 66: 561 - 563)
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